Is VPS45 p.Arg433= (c.1297C>A) pathogenic?

VPS45 p.Arg433= (c.1297C>A) is classified Likely benign in VPS45 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-31). Ultra-rare (popmax 0.096%, afr); Associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome.

What condition is associated with VPS45 p.Arg433= (c.1297C>A)?

VPS45 p.Arg433= (c.1297C>A) is associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome (ClinVar).

How common is VPS45 p.Arg433= (c.1297C>A) in the general population?

VPS45 p.Arg433= (c.1297C>A) is ultra-rare (popmax 0.096%, afr) (gnomAD).

VPS45 p.Arg433=

Q: How is Congenital neutropenia-myelofibrosis-nephromegaly syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1297C>A · rs140771138 · VCV1147226

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.096%, afr)

Conditions

congenital neutropenia-myelofibrosis-nephromegaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.91, phastCons 1
Overall
CADD	10.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.096% African / African-American · 72/75,016 alleles

Filtering AF 0.0781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0716%

Overall 0.00465% 75/1,614,060 alleles · ultra-rare exomes 39/1,461,836 · genomes 36/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.096%	1,042
Remaining individualsnot grpmax-eligible	0.0032%	31,252
Admixed American	0.00167%	60,002

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VPS45
Protein: p.Arg433=
Coding: c.1297C>A
MANE Select: NM_007259
dbSNP: rs140771138
Type: single nucleotide variant
Location: chr1:150092335 (GRCh38)
Gene constraint: LOEUF 0.629 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.65

Full VPS45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital neutropenia-myelofibrosis-nephromegaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital neutropenia-myelofibrosis-nephromegaly syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VPS45 p.Arg433Gln Uncertain significance ★★ ⚠ same residue
VPS45 p.Arg433Ter Likely pathogenic ★ same residue
VPS45 p.Glu238Lys Likely pathogenic ★★ same condition
VPS45 p.Thr224Asn Pathogenic ★★ same condition
VPS45 c.687+5A>G Uncertain significance ★★ same condition
VPS45 p.Ala392Thr Uncertain significance ★★ ⚠ same condition
VPS45 p.Ala445Gly Uncertain significance ★★ ⚠ same condition
VPS45 p.Ala567Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vps45-p-arg433 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown